PROJECT SUMMARY/ABSTRACT: The candidate is a geriatric psychiatrist with previous basic science training in molecular neurodegeneration who is applying for a K23 Mentored Patient-Oriented Career Development Award to transition to full independence as a clinical research scientist. The training goals?gaining expertise in positron emission tomography (PET) neuroimaging-clinical correlations, clinical research methodology and analytic methods, and cognitive and behavioral assessments in older adults?will together enable the candidate to emerge as a fully independent clinician scientist in geriatric psychiatry at the interface of late life depression and preclinical Alzheimer?s Disease (AD).These training goals are aligned with the aims of the proposed project, which focuses on late life depressive symptoms in the pathogenesis of preclinical AD. Despite the prevalence of late life depressive symptoms and AD, the associations among depressive symptoms, in vivo amyloid and tau, and early clinical manifestations of AD (e.g., subjective cognitive decline, subtle decline on sensitive cognitive tests) have not been clearly established. This project will fill a critical gap in knowledge by determining whether the presence (vs absence) of depressive symptoms predicts greater accumulation of AD proteinopathies, amyloid and tau, and more rapid clinical progression. Preliminary data generated through competitive pilot funding to the applicant showed a modest cross-sectional association between increased subclinical depressive symptoms and increased inferior temporal tau (measured using a promising tau PET ligand Flortaucipir [FTP]) in cognitively normal (CN) older adults in the Harvard Aging Study (HABS), one of the best characterized longitudinal cohorts of preclinical AD. However, further investigation across a wider range of depressive symptoms and with longitudinal follow up is needed to more definitively address this question. The overarching hypothesis of the current study is that depressive symptoms, whether cause or consequence of AD pathology, occur late in preclinical AD and are a marker for greater tau accumulation and clinical progression over time. To test this hypothesis, we will investigate the cross-sectional association of depressive symptoms and in vivo cortical amyloid using Pittsburgh compound B (PiB) PET imaging and tau using FTP PET. We will additionally investigate whether baseline severity of depressive symptoms and cortical amyloid predict greater tau accumulation over three-year follow up. Finally, we will recruit a new pilot cohort of participants of comparable cognitive status to HABS but with moderate to severe depressive symptoms in order to investigate whether depressive symptom severity modifies the relationship between tau and clinical manifestations of AD over three-year follow up. Together, these aims have promise to impact the design and future success of prevention trials in older adults who may be at greatest risk for AD, and will result in the candidate?s transition to independence as a clinician-scientist in geriatric psychiatry working at the interface of late life depression and AD. !